Despite continued reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade. In the face of this the pressing unmet need, there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression (IS) in kidney and liver transplantation. Clinical endpoints include efficacy and safety and the trial will systematically assess whether avoidance of CNI-based maintenance IS with efalizumab provides superior preservation of renal structure and function and lower rates of PTDM, hypertension, and dyslipidemia relative to a tacrolimus-based regimen. The studies will be heavily leveraged to gain mechanistic insight regarding the etiology of native renal injury and IFTA and to develop proteomic or gene expression biomarkers of progressive renal injury. We will develop clinically relevant, mechanistically based, non-invasive assays for the early detection of renal injury with the goal of translating our findings into practical tools aiding the clinician in patient care. We will acquire important data on the impact of efalizumab and tacrolimus on protective immunity by systematically defining the type and pattern of viral reactivation observed with each regimen, as well as assessing the impact on peripheral lymphocyte homeostasis and the phenotype and function of virus-specific memory T cells. We will determine whether ongoing exposure of the recipient to donor-antigens under the sustained blockade of LFA-1 with efalizumab while avoiding CNI will result in alterations in anti-donor T cell and/or humoral immunity or an Increased Incidence of recently described tolerance signatures. Given the prevalence of renal injury (native and allograft) and centrality of immune function across all transplant settings regardless of IS regimen, we anticipate broad applicability of these goals. We have aligned three high volume transplant hospitals with extensive experience in clinical transplant studies and recruited investigators with substantial, published experience in human transplant immunobiology to insure that our studies will yield clinically meaningful and mechanistically important results. RELEVANCE: Despite reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade and there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression in kidney and liver transplantation.